Prognostic factors associated with a restricted mouth opening (trismus) in patients with head
and neck cancer
van der Geer, Sarah J.; van Rijn, Phillip V.; Roodenburg, Jan L. N.; Dijkstra, Pieter U.
Published in:Head and Neck: Journal of the Sciences and Specialties of the Head and Neck
DOI:
10.1002/hed.26327
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van der Geer, S. J., van Rijn, P. V., Roodenburg, J. L. N., & Dijkstra, P. U. (2020). Prognostic factors associated with a restricted mouth opening (trismus) in patients with head and neck cancer: Systematic review. Head and Neck: Journal of the Sciences and Specialties of the Head and Neck, 42(9), 2696-2721. https://doi.org/10.1002/hed.26327
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C L I N I C A L R E V I E W
Prognostic factors associated with a restricted mouth
opening (trismus) in patients with head and neck cancer:
Systematic review
Sarah J. van der Geer DMD
1|
Phillip V. van Rijn DMD
1|
Jan L.N. Roodenburg DMD, PhD
1|
Pieter U. Dijkstra PT, PhD
1,21Department of Oral and Maxillofacial
Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
2Department of Rehabilitation, University
of Groningen, University Medical Center Groningen, Groningen, The Netherlands
Correspondence
Sarah J. van der Geer, Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. Email: s.j.van.der.geer@umcg.nl
Abstract
Background: To prescribe early trismus therapy, prognostic factors influenc-ing the restricted mouth openinfluenc-ing should be identified first. Our aim is to pre-sent an overview of these factors in patients with head and neck cancer. Methods: PubMed, Cochrane, EMBASE, and CINAHL were searched using terms related to head and neck cancer and mouth opening. Risk of bias was
assessed using the“Quality in Prognosis Studies” tool. A best evidence
synthe-sis was performed.
Results: Of the identified 1418 studies, 53 were included. Three studies con-tained a prognostic multivariate model for a restricted mouth opening.
Conclusions: Patients with head and neck cancer will most likely develop a restricted mouth opening when they have a large tumor near the masticatory muscles that requires extensive cancer treatment. A restricted mouth opening most likely occurs within 6 months after cancer treatment. Further research is necessary on factors related to healing tendency or pain intensity.
K E Y W O R D S
head and neck neoplasms, mouth neoplasms, mouth opening, oral, prognosis, surgery
1
|
I N T R O D U C T I O N
Trismus, a restricted mouth opening, is considered to be one of the three most burdensome side effects after head
and neck cancer treatment.1-3 Daily activities, such as
speaking, eating, and swallowing become more difficult.4-6
As a consequence, trismus impacts the quality of life.7,8
In order to prevent or to treat trismus, stretching
regi-mens are often prescribed to increase mouth opening.9In
2016, a systematic review analyzed the effects of various stretching regimens, but none of them was found to be
superior.10It has been suggested that early initiation of a
therapy for trismus results in a greater improvement in
mouth opening.11However, when the effectiveness of an
early, preventive stretching regimen was analyzed, no sig-nificant difference between the exercise group and
con-trol group was found.12 Not all the patients may have
been at risk for trismus, which would have hindered the detection of the effectiveness of the therapy. Moreover, the group of patients not at risk of developing trismus
Registration: Prospero CRD42017071400.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2020 The Authors. Head & Neck published by Wiley Periodicals, LLC.
was unnecessarily burdened with an intensive stretching regimen.
Thus, factors influencing trismus should be identified so that only the patients at risk for trismus are subjected to therapy. Previous studies examined the factors associ-ated with trismus but the criteria they applied varied (eg,
a maximal mouth opening [MMO] of less than 20 mm13
or less than 35 mm14). They used different assessment
methods (eg, objective measurement using a millimeter
scale15,16 or perceived difficulties opening the mouth
using questionnaires17,18), or different study populations
(eg, patients receiving radiotherapy15,19 or
chemoradiotherapy19,20). There is no recent systematic
review available on prognostic factors for trismus in patients with head and neck cancer in general.
The aim of this systematic review is to identify the prognostic factors for trismus (measured objectively and subjectively) in patients treated for head and neck cancer.
2
|
M A T E R I A L S A N D M E T H O D S
The protocol for this systematic review is registered in Pros-pero (Register code: CRD42017071400). The study will be reported according to the Preferred Reporting Items for Sys-tematic Reviews and Meta-Analyses (PRISMA) statement.
2.1
|
Literature search
Four databases were searched for eligible studies:
PubMed, Cochrane, Excerpta medica dataBASE
(EMBASE), and Cumulative index to nursing and allied health literature (CINAHL). The search strategy was developed in cooperation with an information specialist and included MesH terms and free text regarding head and neck cancer and mouth opening (Supplementary Information S1). All the databases were searched in November 2017. An update was performed in July 2019.
2.2
|
Eligibility criteria
Prospective longitudinal studies were included if at least two measurement moments, regarding objective mea-surements of trismus (trismus and MMO) or subjective assessments of trismus (perceived difficulties with open-ing the mouth), were reported. No distinction was made between active or passive mouth opening measurements. Studies of trismus therapies were excluded, unless they reported data on a restricted mouth opening of a control group that did not receive a form of trismus therapy. (Sys-tematic) reviews, in vitro studies, comments, letters to
the editor, and case reports of less than 10 patients were excluded. There were no language or time restrictions. Studies written in languages that could not be understood by the authors were translated. Additionally, a full-text version had to be available in order to be included for fur-ther assessment and data extraction.
2.3
|
Study selection
After removing any duplicates, the titles and abstracts were assessed for inclusion independently by J.G., P.R., and P.D. The assessors J.G. and P.D. independently assessed the full text versions for inclusion. Any disagree-ments between them were resolved by discussion. In case no consensus could be reached, a third observer (K.D.) was consulted. Interobserver reliability was measured through Cohen's kappa and percentage of agreement.
Google Scholar, the references of the relevant system-atic reviews and the references of the eligible studies were checked by J.G. for studies missed in the database search. When a study was considered eligible, the full text paper was screened and assessed by J.G. and P.D. inde-pendently, according to the original protocol.
The studies that only reported descriptive data and did not perform any statistical tests to analyze the influ-ence of factors on trismus, MMO, or perceived difficulties opening the mouth, were excluded.
2.4
|
Data extraction
One reviewer (J.G.) extracted all required information from the studies, which included sample size, patient characteristics (age, sex), tumor characteristics (tumor localization, T classification, N classification, tumor stage, histology), treatment characteristics (treatment modality), and method of outcome measurements (number of measurement points reported, follow-up time). Percentage of patients with trismus (based on a cut-off point), difference in means or medians of MMO between two measurements (one measurement after treatment minus measurement before treatment) were recorded. In case of multivariate prognostic models, the estimated effects and 95% confidence intervals were extracted. Data of the univariate analysis or multivariate analysis were extracted in case trismus, mouth opening, difficulties opening the mouth, were analyzed over time. A second reviewer (P.D.) extracted data from a ran-dom sample of eight studies containing only univariate analyses and the three studies containing multivariate analyses. In case any data were missing or needed clarify-ing, the corresponding authors were contacted by e-mail.
2.5
|
Risk of bias assessment
Included studies were assessed by J.G. and P.D. on risk of
bias using the “Quality In Prognosis Studies” tool
(QUIPS).21This tool is designed to assess the risk of bias
in prognostic studies. The tool assesses the following items: study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, and statistical analysis and reporting. The risk of bias can be scored low, moderate, or high. We added the option “not applicable” which could be chosen in case the studies did not provide adequate information to be able to assess that specific domain. As attrition is commonly high in studies including patients with head and neck cancer due to early decease, we predefined the following criteria: when the study attrition is more than 20%, but no specifi-cations are given, we assessed the study as high risk of bias on the study attrition domain. When the study attrition is more than 20%, but specifications are given, we assessed the study as moderate risk of bias on the study attrition domain. For the statistical analysis and reporting domain, we scored a high risk of bias if the effect of only one factor on restricted mouth opening was analyzed. J.G. and P.D. were authors of two studies. These studies were assessed by two independent assessors, K.D. and B.G., to reduce the risk of assessor bias.
To assess the overall risk of bias of a study, it was
recommended to score the overall risk of bias as “low”
if at least all, or the most important domains (deter-mined a priori), were rated as having a low risk of
bias.21On that basis, we determined the overall risk of
bias to be low, if at least five out of six domains were
scored with a low risk of bias and the domains“study
confounding” and “statistical analysis and reporting”
were scored with a low risk of bias. These two domains are of major importance for analyzing the influence of factors on trismus, MMO or perceived difficulties open-ing the mouth.
In case of disagreement between the reviewers, a con-sensus meeting was held. If no concon-sensus could be reached, a third reviewer (K.D.) gave a binding verdict.
2.6
|
Best evidence synthesis
Due to clinical and methodological heterogeneity between the included studies, we did not perform a meta-analysis. Instead, we performed a best evidence synthesis. Three main domains were taken into account in order to rate the
level of evidence: quality, quantity, and consistency.22,23
We determined the evidence to be strong if two or more studies (quantity) with an overall low risk of bias (quality) and relatively consistent findings (consistency) of the
analyzed factors across the studies was found. Evidence was determined to be moderate when evidence was pro-vided including one study with an overall low risk of bias and relatively consistent findings of the analyzed factors across the studies. Evidence was determined to be limited when evidence was provided by studies with an overall high risk of bias and relatively consistent findings of the analyzed factors across the studies. Evidence was deter-mined to be limited/moderate when evidence was pro-vided by a study with an overall high risk of bias, but in which a multivariate prognostic model was presented. The evidence was determined to be conflicting in case there were inconsistencies between the findings of the analyzed factors found across the studies.
3
|
R E S U L T S
3.1
|
Study selection
The first search resulted in 1703 hits. After duplicate removal, 1199 papers were included for title and abstract assessment (Cohen's kappa: 0.533, agreement 90%). Although 141 were deemed suitable for full text assess-ment after a consensus meeting (Cohen's kappa: 0.577, agreement 81%), 40 papers were excluded: 37 were abstracts only (eg, conference abstract or poster abstract), one was a review, one was a comment in a forum, and one full-text could not be retrieved. The corresponding author was requested to provide the full text article, but no response was received. A further 59 of the available full text papers were excluded because they did not fulfill the inclusion criteria.
The additional check in Google Scholar and the refer-ences of the relevant studies and (systematic) reviews,
resulted in 16 other papers.5,17,24-37After reading the full
text, two did not meet the inclusion criteria.20,24A total
of 56 studies were included for risk of bias assessment and data extraction. During the data extraction process, an additional seven studies were excluded, because no statistical analysis was performed to identify any factors
influencing trismus (n = 4)27,38-40or because exercises to
increase mouth opening had been undertaken
(n = 2),26,41or because only one measurement moment
was reported (n = 1)42(Figure 1).
After an update of the search and the removal of duplicates, 203 additional papers were identified. After assessing the titles and abstracts (Cohen's kappa: 0.378, agreement 80%), were included for assessment of the full text (Cohen's kappa: 0.493, agreement 76%). Eventually,
four of those studies were included.43-46
The above procedures resulted in a final selection of
3.2
|
Study characteristics
Sample sizes ranged from 14 to 641 patients (Table 1). The number of measurement moments ranged from 2 to 20. The longest follow-up period was 5 years.
3.3
|
Risk of bias assessment
The overall Cohen's kappa bias assessment score was 0.310 (52% agreement). The source or study population was not described (adequately) in the majority of the
studies. These studies were scored with “N/A” on the
study participation domain (n = 32; 60%)
(Table 2).
5,13,16,18,20,28,30,32,36,37,43,45-47,51-58,60,61,64,65,68,69,72,73,75,77
Eleven studies (21%) did not
report attrition rate.13,19,33,35,51,55,61,70,72,73,77Some did not
report the attrition rate because only the patients with complete data were included. Four studies (8%) were
scored with “N/A" on the outcome measurement
domain14,16,55,60: two studies did not describe the
mea-surement method55,60 and two studies used a
measure-ment method that has not been validated (extra-oral
measurements).14,16 The majority of the studies were
scored with a high risk of bias concerning the statistical analysis and reporting domain (n = 42; 79%) because
they lacked a multivariate analysis.
5,13,14,17,18,20,28-37,43,45-47,51,52,54-58,60-68,70,72-75,77
3.4
|
Distinguishing the outcome
measurements
A distinction was made between objective (eg, using a ruler or calliper) or subjective (eg, using a patient' ques-tionnaire) assessments of restricted mouth opening. An additional distinction was made between the objective studies, namely using a restricted mouth opening as a
cut-off point (n = 6)13,14,47-50or a decrease in MMO
mea-sured in millimeters (n = 16).15,16,43,51-63
The subjective analyses assessed the perception of a restricted mouth opening either using the European Orga-nization for Research and Treatment for Cancer Quality of Life Questionnaire Head & Neck module- 35 (EORTC
QLQ H&N35) (n = 29)17,18,20,28-37,45,46,64-77 or an
adden-dum similar to the EORTC QLQ H&N35 (n = 1)5or
Com-mon Terminology Criteria for Adverse Events (n = 1).19
The Gothenburg Trismus Questionnaire (n = 3) was used
as a secondary endpoint to assess trismus.48,49,63
3.5
|
Univariate analyses
In 16 studies, a single prognostic factor for a decrease in MMO and the patients' perception of difficulties with
opening the mouth was analyzed over time
(Table 3).14,16,35,43,46,53-58,62,65,71,72,74 Regarding patient
related factors, a significant effect was found in relation to sex (in one study in the period between before and
after treatment)14 and the −509 genotype.56 Patients
with a homozygous T allele (TT) in the−509 genotype
had a greater reduction in MMO than those with a homozygous C allele (CC) or heterozygous C allele (CT). Tumor related factors included large reductions in MMO when the tumor was located near the oral cavity
or oropharynx.53,54 Less reduction was found in other
areas, such as the nasopharynx, hypopharynx, larynx, or
lymph drainage areas.53,54 No significant effects were
found in relation to T classification or N
classifica-tion.14,16,65Cancer treatment also resulted in a reduction
in MMO, with the most occurring after
chemoradiotherapy and the least after surgery.14 The
MMO decreased directly after surgery but increased in F I G U R E 1 Flowchart. *: 40 studies were not available,
because 37 were abstracts only (eg, conference abstract or poster abstract), one was a review, one was a comment in a forum, and one full-text could not be retrieved
TA BLE 1 Data extraction objective and subjective measurements Author (year) Sample size (no. of patients) Age mean (SD) OR Median (range)
Ratio male: female
Histology Tumor localization Stage Treatment modality a no. of measures b Follow-up c Remarks Objective measurements — cut-off point for trismus Yan et al (2003) 13 112 44.6 [14-71] 83:29 – Nasopharynx I-IV RT 76 0 Scott et al (2011) 14 64 59 (10) 40:24 SCC Oral cavity, oropharynx T:1-4 N:0,+ S, (C)RT 3 6 Lee et al (2012) 47 152 –– – HNC Disease:1-4 S ,(C)RT 3 > 6 Pauli et al (2013) 48 75 62 [35-86] 45:30 – HNC T:0-4 UICC:I-IV S,(C)RT 4 1 2 P : Pauli et al (2016) 49 Pauli et al (2016) 49 216 60 [29-87] 155:62 – HNC T:x-4 (C) RT 41 2 van der Geer et al (2016) 50 641 62.3 (12.5) 451:190 – HNC T:x-4 S,(C) RT 7 4 8 T : Kamstra et al (2015) 15 Objective measurements — maximal mouth opening measurements Goldstein et al (1999) 51 58 –– – HNC – RT 2 6-12 Wang et al (2005) 52 17 <50 y (n = 8), >50 y (n = 9 ) 13:4 – Nasopharynx T:1-4 N:0-3 Disease:I-III RT 20 48 Bragante et al (2012) 54 26 59.0 (8.8) [45-74] 26:0 – HNC INCA:I-IVB (C) RT 30 Mucke et al (2012) 55 96 62.8 (8.9) [41-82] 58:38 SCC anterior floor of the mouth T:1-4 N:0-3 S, (C)RT 2 2-24 Lyons et al (2013) 56 62 <50 y (n = 26), ≥ 50 y (n = 36) d 33:29 – HNC T:1-4 N:0-3 S,(C) RT 2 12-36 Lazarus et al (2014) 57 29 58.5 (9.2) [41-78] 23:6 – HNC AJCC:I-IVA (C)RT 36 Safdar et al (2014) 58 65 Group 1: 59.7 (11.5) Group 2: 60.6 (13.4) 45:20 – HNC T:1-4 S 2 6 Group 1: platysma reconstruction Group 2: submental reconstruction Wetzels et al (2014) 16 143 Group 1: 68.4 (12.2) Group 2: 66.9 (12.6) Group 1: 17:17 – Oral cavity T:1-4 S,RT 4 1 2 Group 1: maxilla Group 2: mandible (Continues)
TA BLE 1 (Continued) Author (year) Sample size (no. of patients) Age mean (SD) OR Median (range)
Ratio male: female
Histology Tumor localization Stage Treatment modality a no. of measures b Follow-up c Remarks Group 3: 62.3 (12.9) Group 2: 28:26 Group 3: 33:22 Group 3: tongue/ floor of mouth Bragante et al (2015) 53 56 58.7 (10.8) 52:4 – UADT Disease:I-IV S,(C) RT 20 Fong et al (2015) 59 27 58.7 (9.5) 16:11 – Nasopharynx AJCC:I-IV S,(C) RT 4 1 2 (after intervention) Control Group only Kamstra et al (2015) 15 641 62.3 (12.5) 451:190 – HNC T:0-4, N:0-3 S,(C) RT 74 8 Manaktala et al (2015) 60 24 –– – HNC – RT 51 8 G y Nayar et al (2016) 61 55 –– – HNC – S, RT 2 1-2 Al-Saleh et al (2017) 43 16 Group 1: 54.2 (12.5) Group 2: 50.6 (11.9) Group 1: 6:3 Group 2:5:2 – Oral cavity, oropharynx T:1-4 N:0-3 S 2 1.5-2 Group 1: mandibulotomy surgery Group 2: transoral surgery Lalla et al (2017) 62 372 59.8 (10.9) 284:88 SCC HNC – S,(C) RT 26 Thor et al (2017) 63 196 60 (11) 141:55 – HNC T:0-4 N:0-4 (C) RT 4 1 2 P : Pauli et al (2016) 49 Subjective measurements De Graeff et al (1999) 17 75 60 [29-75] 54:21 SCC Oral cavity, oropharynx AJCC:I-IV S, RT 3 1 2 P : D e Graeff et al (2000) 29 De Graeff et al (2000) 29 107 60 [31-73] 86:21 SCC HNC AJCC:0-IV S,RT 5 3 6 Epstein et al (2000) 5 20 53.4 [38-78] 12:8 – HNC AJCC:I-IV RT 36 357 63 [18-88] 256:101 – HNC Disease:I-IV S,(C)RT 6 1 2
TA BLE 1 (Continued) Author (year) Sample size (no. of patients) Age mean (SD) OR Median (range)
Ratio male: female
Histology Tumor localization Stage Treatment modality a no. of measures b Follow-up c Remarks Bjordal et al (2001) 28 Hammerlid et al 2001) 18 232 61 [18-85] 162:70 – HNC Disease:I-IV S,(C)RT 5 3 6 Ohrn et al (2001) 33 18 55.4 (9.0) [38-73] 10:8 SCC ACA HNC – (C) RT 41 Wiltfang et al (2003) 34 53 54.2 [34-78] 48:5 SCC Oral cavity UICC:0-IV S ,(C) RT 42 4 Fang et al (2004) 30 77 50 [22-78] 77:0 SCC HNC AJCC:III,IV S, RT 2 2 4 P : Fang et al (2005) 31 Abendstein et al (2005) 64 167 61 [18-86] 116:51 – HNC Disease:I-IV S,(C)RT 3 6 0 P : Bjordal et al (2001) 28 Fang et al (2005) 31 149 53 [25-81] 138:11 SCC HNC AJCC:III,IV (C) RT 21 2 Nordgren et al (2005) 32 89 60 68:21 – Pharynx Disease:I-IV S,(C) RT 4 6 0 P : Bjordal et al (2001) 28 Urdaniz et al (2005) 37 60 Group 1: 56 Group 2: 57 –– HNC T:2-4 N:0,+ AJCC:III,IV (C)RT 3 1 Group 1: 72 Gy, 6w k Group 2: 80.4 Gy, 7w k Borggreven et al (2007) 65 80 58 [23-74] 47:33 SCC Oral cavity, oropharynx T:2-4, N:0-3 S, RT 3 1 2 Oates et al (2007) 20 14 –– – Nasopharynx T:1-4 N:0-3 (C)RT 52 4 Bozec et al (2008) 66 65 61.2 (9.3) [40-85] 49:16 – HNC T:2-4 N:0-3 S, RT 3 1 2 Bozec et al (2009) 67 41 62.3 (9.6) [43-85] 33:8 SCC Oral cavity, Oropharynx T:2-4 N:0-3 AJCC:II-IV S ,(C)RT 3 1 2 P : Bozec et al (2008) 66 Rizvi et al (2009) 68 37 51.8 (9.6) 18:19 – HNC T:3,4 N:1,2 S, RT 4 6 (Continues)
TA BLE 1 (Continued) Author (year) Sample size (no. of patients) Age mean (SD) OR Median (range)
Ratio male: female
Histology Tumor localization Stage Treatment modality a no. of measures b Follow-up c Remarks Vergeer et al (2009) 35 241 Group 1: ≤ 65 y (n = 95), >65 y (n = 55) Group 2: ≤ 65 y (n = 68), >65 y (n = 23) Group 1: 104:46 Group 2: 51:40 SCC HNC T:0-4 N:0-3, UICC:I-IV S,(C) RT 5 1 2 Group 1: 3D-RT Group 2: IMRT Yoshimura et al (2009) 69 56 63 [25-88] 46:10 SCC Oral cavity T:1-3 LDR-BT 41 2 Chan et al (2012) 36 185 50.2 (11.4)[24-81] 151:34 – Recurrent nasopharynx – S,(C)RT 26 Al-Mamgani et al (2013) 70 207 <65 y (n = 142), ≥ 65 y (n = 65) 143:64 – Oropharynx T:1-4 N:0-3 AJCC:I-IV (C) RT 51 8 Kumar et al (2013) 74 111 Group 1: 55.3 (12.4) Group 2: 53.4 (11.2) Group 1: 47:8 Group 2: 49:7 SCC HNC Stage:III-IVb (C) RT 3 6 Group 1: palliative RT Group 2: palliative CRT Rathod et al (2013) 71 60 Group 1: 55 [33-65] Group 2: 51 [31-65] Group 1: 25:3 Group 2: 29:3 SCC HNC T:1-3 N:0-2b AJCC:I-IV RT 6 2 4 Group 1: 3D-RT Group 2: IMRT Zhao et al (2014) 72 83 Group 1: 52.0 [22-81] Group 2: 53.4 [28-76] Group 1: 28:15 Group 2: 27:13 – Nasopharynx T:4 N:3 UICC:2-4 (C)RT 5 2 4 Group 1: CRT + ERF Group 2: CRT Arslan et al (2015) 73 40 56 [20-65] 33:7 – HNC Stage:I-IVA S,(C) RT 33 Landstrom et al (2015) 75 19 56.6 12:7 SCC ACA HNC T:1,2 (C) RT 2 1 2 Rao et al (2016) 19 421 ≤ 55 y (n = 191), >55 y (n = 230) 345:76 SCC Pharynx, larynx T:1-4 N:0-3 AJCC:II-IV (C)RT 12 Median 33 Dzioba et al (2017) 76 117 58.2 (13.3) 71:46 SCC Tongue (oral cavity) T:1-4 AJCC:I-IVA S, (C)RT 4 1 2
TA BLE 1 (Continued) Author (year) Sample size (no. of patients) Age mean (SD) OR Median (range)
Ratio male: female
Histology Tumor localization Stage Treatment modality a no. of measures b Follow-up c Remarks Gao et al (2018) 77 77 <60 y (n = 48), ≥ 60 y (n = 29) 41:36 SCC ACC Tongue – S 31 2 Tribius et al (2018) 46 161 60.4 (10.4) 110:51 HNC UICC T:1-4 N:0-3 RT 32 4 B L = A T Veluthattil et al (2019) 45 25 ≤ 60 y (n = 21), >60 y (n = 4 ) 11:14 SCC Oral cavity Stage:IVA- IVC RT 22 Abbreviations: Histology : ACA, adenocarcinoma; ACC, adenoid cystic carcinoma; SCC, squamous cell carcinoma. Tumor localization : HNC, head and neck cancer; UADT. upper aero-digestive tract. Stage : AJCC, stage according to American Joint Committee on Cancer; INCA, stage according to Instituto Nacional de Câncer (National Institute of Cancer B razil); N, nodes classifica-tion; T, tumor classification; UICC, stage according to Union for International Cancer Control. Treatment modality : C , chemotherapy; (C)RT, chemoradiotherapy; LDR-BT, low-dose-rate inter-stitial brachytherapy; RT, radiotherapy; S, surgery. Remarks : 3D-RT, three-dimensional radiotherapy; ERF, extracorporeal radiofrequency; IMRT, intensity modulated radiotherapy; Gy, Groupay of radiation; P, partial overlap of study population; T, total overlap of study population; wk, week. aThe text in bold indicates that all the patients in this study received that particular treatment modality. bNumber of measurement points reported. cFollow-up period (in months after treatment). dCalculated from data reported.
T A B L E 2 Quality assessment using the“Quality in Prognosis Studies” tool Author (year) Study participation Study attrition Prognostic factor measurement Outcome measurement Study confouding Statistical analysis and reporting Overall risk of bias Objective measurements
Yan et al (2003)13 N/A N/A L L H H H
Scott et al (2011)14 H H L N/Aa L H H
Lee et al (2012)47 N/A H L L M H H
Pauli et al (2013)48 M L L L L M H
Pauli et al (2016)49 L M M L M M H
van der Geer et al (2016)50 M H L L M L H Objective measurements Goldstein et al (1999)51 N/A N/A L L M H H Wang et al (2005)52 N/A M L L H H H Bragante et al (2012)54 N/A M L L M H H
Mucke et al (2012)55 N/A N/A L N/A H H H
Lyons et al (2013)56 N/A M L M L H H
Lazarus et al (2014)57 N/A M L L H H H
Safdar et al (2014)58 N/A L L L H H H
Wetzels et al (2014)16 N/A M L N/Aa L L H
Bragante et al (2015)53 N/A L L L L L L Fong et al (2015)59 H M L L H M H Kamstra et al (2015)15 L H L M M L H Manaktala et al (2015)60 N/A L L N/A H H H
Nayar et al (2016)61 N/A N/A L L H H H
Al-Saleh et al (2017)43 N/A H L M H H H Lalla et al (2017)62 H H L M H H H Thor et al (2017)63 M H L L H H H Subjective measurements De Graeff et al (1999)17 L M L L H H H De Graeff et al (2000)29 L M L L M H H Epstein et al (2000)5 N/A H L L M H H Bjordal et al (2001)28 N/A L L L H H H Hammerlid et al 2001)18 N/A L L M L H H Ohrn et al (2001)33 M N/A L L H H H Wiltfang et al (2003)34 L M L L H H H Fang et al (2004)30 N/A M L L H H H Abendstein et al (2005)64 N/A L L L M H H Fang et al (2005)31 L L L L H H H
the 6 months thereafter. When patients received (chemo) radiotherapy, the MMO decreased directly after the treatment, but did not increase in the 6 months thereafter. The MMO decreased even more with an
increase in radiation dose.54
Patients who were given conventional three-dimen-sional radiotherapy, instead of intensity modulated
radio-therapy, perceived more difficulties opening the
mouth.35,71Also, patients who underwent chemotherapy
without the addition of extracorporeal radiofrequency perceived more difficulties with opening the mouth com-pared with those who received additional extracorporeal
radiofrequency.72 Regarding the remaining factors, a
greater reduction in MMO was found when mucositis was present compared to when mucositis was not
pre-sent.53MMO was not significantly reduced in relation to
alcohol consumption and smoking factors.16 Patients
with a lower social economic status perceived more diffi-culties with opening the mouth than patients with a
mid-dle or high social economic status.46
3.6
|
Timing
The highest percentage of patients developed trismus directly after treatment and it continued to increase in the 6 months thereafter (Figure 2A). The percentage of patients with trismus seemed to stabilize 12 months after treatment. MMO decreased directly after treatment and in the 6 months thereafter (Figure 2B) and appeared to stabilize 12 months after treatment. Patients' perception of difficulties with opening the mouth was highly diverse T A B L E 2 (Continued) Author (year) Study participation Study attrition Prognostic factor measurement Outcome measurement Study confouding Statistical analysis and reporting Overall risk of bias Nordgren et al (2005)32 N/A M L L M H H Urdaniz et al (2005)37 N/A L L L M H H Borggreven et al (2007)65 N/A L L L M H H Oates et al (2007)20 N/A L L L H H H Bozec et al (2008)66 L H L L L H H Bozec et al (2009)67 L M L L L H H Rizvi et al (2009)68 N/A L L M H H H Vergeer et al (2009)35 M N/A L L H H H Yoshimura et al (2009)69 N/A M M L L M H Chan et al (2012)36 N/A L L L H H H Al-Mamgani et al (2013)70 L N/A L L M H H Rathod et al (2013)71 L H L L L L L
Zhao et al (2014)72 N/A N/A L L H H H
Arslan et al (2015)73 N/A N/A L L H H H
Kumar et al (2013)74 L L L L H H H Landstrom et al (2015)75 N/A L L L H H H Rao et al (2016)19 H N/A L M L L H Dzioba et al (2017)76 L H L L M M H
Gao et al (2018)77 N/A N/A L L H H H
Tribius et al (2018)46 N/A L N/A L H H H
Veluthattil et al (2019)45
N/A M L L H H H
Abbreviations: H, high risk of bias; L, low risk of bias; M, moderate risk of bias; N/A, not applicable.
a
(Figure 2C). The majority of the patients perceived diffi-culties with opening the mouth directly after treatment, but thereafter the perception varied considerably.
The figures were based on 29 studies. Other studies were not included because: they did not report data on restricted mouth opening at time points before and after
oncological treatment (n = 14)
19,34-36,43,46,49,51,55,56,59,61,72,74
; the trismus scores were reported
as a cumulative incidence13; MMO was reported as a
nor-malized value52; a mean reduction58; or as a median
score14; or the scores of the questionnaires were not
transformed into symptom scores (n = 3)5,44,68 or were
reported as a median score.45,75 The data from studies
that included the same study population as another study
were not displayed either.50
3.7
|
Multivariate analyses
Eight studies built multivariate models affecting trismus,
mouth opening perceived difficulties opening the
mouth.15,16,19,48-50,53,76 Three of these studies built and
reported prognostic models taking time into account
(Table 4).15,53,76 Two of these studies analyzed factors
affecting MMO,15,53 and one study analyzed the factors
affecting perceived difficulties with opening the mouth.76
Presence of mucositis, deterioration of overall function-ing (accordfunction-ing to the Karnofsky Performance Status Scale), tumors located near the oral cavity, oropharynx and nasopharynx, nasal cavity and maxillary sinus, shorter time after radiotherapy, female sex, a small base-line mouth opening, large tumor (T stage 4), higher age, and a great target volume (radiotherapy) were signifi-cantly associated with a decrease in MMO. A combina-tion of oncological treatment modalities (surgery and (chemo) radiotherapy) and shorter time after oncological treatment) were associated with perceived difficulties with opening the mouth.
3.8
|
Best evidence synthesis
There is moderate evidence that the presence of mucositis and a deterioration of overall functioning (according to the Karnofsky Performance Status Scale) results in a reduction of MMO (Table 5). There is limited to moderate evidence that target volume, time after treatment, and baseline mouth opening results in a reduction of MMO, and that time after treatment results in higher scores of perceived difficulties opening the mouth. There is con-flicting evidence that the factors age localization, age, T classification, reconstruction after surgery, different types of treatment modalities, and sex affect MMO, and that the
different types of treatment modalities affect perceived dif-ficulties opening the mouth as well.
Conflicting evidence was mainly the result of a differ-ent categorization of a particular factor across the studies. For instance, a significant association between factor tumor localization and MMO was found, if tumor
locali-zation was categorized in the two categories:“oral cavity
and oropharynx” vs “nasopharynx, hypopharynx and
lar-ynx.”53 However, no significant association was found
between factor tumor localization and MMO, if tumor
localization was categorized in the two categories “oral
cavity” vs “oropharynx.”14
Significant associations were found between a reduc-tion in MMO and the factors: T classificareduc-tion: if stage 4 was compared to other stages; treatment modalities, if multiple treatment modalities were compared to a single treatment modality or (chemo)radiotherapy was compared to surgery more than 6 months after treatment; recon-struction, if platysma flap was compared with a submental flap. A significant association between higher scores on perceived difficulties opening the mouth and the factor treatment modality was found, if multiple treatment modalities were compared to one single treatment modal-ity or chemoradiotherapy was compared to radiotherapy alone. The largest reductions on MMO were found for a greater target volume (limited to moderate evidence) and the presence of mucositis after radiotherapy (moderate evi-dence) (Table 4, estimated effects). The greatest increases for perceived difficulties opening the mouth were found for a combination of treatment modalities given (con-flicting evidence) and time after treatment (limited to moderate evidence) (Table 4, estimated effects).
4
|
D I S C U S S I O N
4.1
|
Key results
A restricted mouth opening is most likely in patients with head and neck cancer who have a large tumor near the masticatory muscles that requires extensive cancer treat-ment. A restricted mouth opening is most likely to occur in the first 6 months after cancer treatment.
4.2
|
Quality of studies
Overall, the quality of the studies was poor. Most studies had a high risk of bias. Two studies had a low risk of bias, but these studies did not build a multivariate prognostic model. Factors that were most likely to affect trismus, MMO, or perceiving difficulties opening the mouth, were identified and described. These studies had moderate,
TA BLE 3 Overview of patient, tumor, treatment, and other characteristics as prognostic factors for decrease in maximal mouth opening (objective) and patie nts' perception of difficulties opening the mouth (subjective) Patient characteristics Time points of analysis Age Sex Dental status − 509 genotype Objective measures Scott et al (2011) 14 <55 55-64 65+ Male Female Dentate Edentulous AT-BT − 11 [− 21; − 2] − 4 [− 13; − 1] − 3 [− 12;1] − 8 [− 16; − 2]a − 2 [− 11;1]a − 6 [− 14; − 2] − 9 [− 22;0] 6M-BT − 6 [− 11;1] − 4 [− 10;3] − 5 [− ] − 5 [− 11;2] − 1 [− 10;3] − 4 [− 10;3] − 10 [− 23;0] Lyons et al (2013) 56 CC − 509 genotype CT − 509 genotype TT –509 genotype AT-BT − 8.5 [− 4.5; −13.0] b − 17.0 [− 8.0; −26.0] b − 26.5 [− 33.0; −15.0] b Wetzels et al (2014) 16 AT-BT − 14.3 (− ) c − 14.9 (− ) c − 13.8 (− ) c − 14.5 (− ) c 6M-BT − 9.0 (− ) c − 9.2 (− ) c − 8.1 (− ) c − 9.3 (− ) c 12M-BT − 8.7 (− ) c − 8.5 (− ) c − 8.1 (− ) c − 8.5 (− ) c Lalla et al (2017) 62 6M-BT − 3.3 (− ) c − 3.0 (− ) c Tumor characteristics Localization Stage Objective measures Scott et al (2011) 14 Oral Oropharynx T-stage 1,2 T-stage 3,4 N-stage 0 N-stage + AT-BT − 7 [− 14; − 2] − 5 [− 16; − 1] − 5 [− 14; − 1] − 9 [− 18; − 1] − 5 [− 14; − 1] − 8 [− 16; − 1] 6M-BT − 4 [− 10;2] − 9 [− ] − 3 [− 10;3] − 9 [− 16;1] − 3 [− 10;3] − 8 [− 13;1] Bragante et al (2012) 54 Mouth Oropharynx Hypopharynx Larynx Drainage area Stage I Stage II Stage III Stage IVA Stage IVB AT-BT − 11.0 (1.7) b − 11.5 (7.8) b − 2.0 (0.0) b − 5.3 (6.3) b − 2.8 (4.5) b − 8.0 (− ) − 0.8 (1.5) − 7.8 (5.9) − 4.5 (5.9) − 6.3 (6.9) (Continues)
TA BLE 3 (Continued) Patient characteristics Time points of analysis Age Sex Dental status − 509 genotype Lazarus et al (2014) 57 Oropharynx Others AJCC 1– 3 AJCC 4 3M-BT − 4.1 (− ) c − 5.0 (− ) c − 3.5 (− ) c − 4.8 (− ) c 6M-BT − 3.8 (− ) c − 6.2 (− ) c − 4.1 (− ) c − 5.0 (− ) c Wetzels et al (2014) 16 Maxilla Mandible TFM (tongue/floor of mouth) T-stage 1 T-stage 2 T-stage 3 T-stage 4 AT-BT − 19.1 (− ) a,c − 15.5 (− ) a,c − 10.7 (− ) a,c − 12.0 (− ) c − 16.7 (− ) c − 17.3 (− ) c − 15.0 (− ) c 6M-BT − 15.1 (− ) a,c − 9.6 (− ) a,c − 5.0 (− ) a,c − 5.7 (− ) c − 10.4 (− ) c − 14.5 (− ) c − 13.8 (− ) c 12M-BT − 11.8 (− ) a,c − 8.1 (− ) a,c − 7.5 (− ) a,c − 7.1 (− ) c − 9.4 (− ) c − 10.8 (− ) c − 12.0 (− ) c Bragante et al (2015) 53 Oral cavity oropharynx r
Nasopharynx Hypopharynx Larynx
r AT-BT − 5.64 (6.42) a − 1.68 (6.27) a Subjective measures Borggreven et al (2007) 65 Oral cavity Oropharynx T-stage 2 T-stage 3,4 6M-BT 10.6 (− ) 24.2 (− ) 23.5 (− ) 14.3 (− ) 12M-6M 5.6 (− ) − 11.5 (− ) − 11.1 (− ) 3.3 (− ) T reatment characteristics Treatment modality Reconstruction Radiation dose Objective measures Scott et al (2011) 14 No RT RT CRT No free-flap Soft-free flap Composite free flap AT-BT − 8 [− 14; − 2] − 5 [− 13;1] − 9 [− ] − 2 [− 9; − 1] − 6 [− 16; − 2] − 11 [− 12;0] 6M-BT − 1 − 7 − 7 − 1 − 5 − 4
TA BLE 3 (Continued) Patient characteristics Time points of analysis Age Sex Dental status − 509 genotype [− 9;4] a [− 15;0] a [− ] a [− 10;4] [− 11;1] [− ] Bragante et al (2012) 54 RT CRT Total dose AT-BT − 5.5 (6.0) − 4.4 (5.5) R = − 0.164 a Mucke et al (2012) 55 S only S + RT S+ RT + ORN AT-BT − 22.5% b − 49.2% b − 49.0% b Safdar et al (2014) 58 Platysma flap Submental flap 6M-BT − 3.7 (− 1.8) a,d − 4.7 (− 1.6) a,d Wetzels et al (2014) 16 S only S + RT RT No surgery Local flap Myocutaneous or free flap Bone graft/ flap AT-BT − 13.4 (− ) a,c − 18.2 (− ) a,c − 7.1 (− ) a,c − 11.1 (− ) c − 22.9 (− ) c − 17.9 (− ) c − 17.4 (− ) c 6M-BT − 4.5 (− ) a,c − 15.0 (− ) a,c − 8.2 (− ) a,c − 5.5 (− ) c − 20.9 (− ) c − 12.9 (− ) c − 12.7 (− ) c 12M-BT − 4.6 (− ) a,c − 13.9 (− ) a,c − 8.0 (− ) a,c − 5.9 (− ) c − 14.6 (− ) c − 11.9 (− ) c − 9.8 (− ) c Al-Saleh et al (2017) 43
Mandibu- lotomy surgery Transoral surgery 1.5-2AT-BT 11.7 (− ) a,c 5.4 (− ) a,c Subjective measures Vergeer et al (2009) 35 3D-RT IMRT 6W-BT 8.8 (− ) b,c − 7. (− ) b,c 6M-BT 11.9 (− ) b,c 1.3 (−) b,c Kumar et al (2013) 74 RT CRT 1M-BT − 3.7 (− ) a,c − 12.3 (− ) a,c 6M-BT 0.0 (− ) a,c − 17.06 (− ) a,c (Continues)
TA BLE 3 (Continued) Patient characteristics Time points of analysis Age Sex Dental status − 509 genotype Rathod et al (2013) 71 3D-RT IMRT 3M-BT 6 (−) b,c − 4 (− ) b,c 6M-BT 16 (−) b,c − 3 (− ) b,c 12M-BT − 2 (− ) b,c − 2 (− ) b,c 18M-BT 2 (−) b,c − 4 (− ) b,c 24M-BT 8 (−) b,c − 9 (− ) b,c Zhao et al (2014) 72 CRT+ ERF CRT 6M-AT − 3.5 (− ) a,c 17.1 (−) a,c 12M-AT − 2.6 (− ) a,c 18.2 (−) a,c 18M-AT − 6.6 (− ) a,c 20.4 (−) a,c 24M-AT − 6.4 (− ) a,c 19.0 (−) a,c Other characteristics Smoking Alcohol (>1 daily) Mucositis SES Objective measures Wetzels et al (2014) 16 Yes No Yes No AT-BT − 12.9 (− ) c − 15.4 (− ) c − 14.8 (− ) c − 14.3 (− ) c 6M-BT − 8.9 (− ) c − 9.1 (− ) c − 9.1 (− ) c − 9.0 (− ) c 12M-BT − 8.9 (− ) c − 8.2 (− ) c − 10.5 (− ) c − 7.6 (− ) c Bragante et al (2015) 53 Yes No AT-BT − 5.9 (6.6) a − 0.6 (5.3) a
TA BLE 3 (Continued) Patient characteristics Time points of analysis Age Sex Dental status − 509 genotype Subjective measures Tribius et al (2018) 46 Low Middle High 24M-AT − 12.3 (− ) a,c − 30.5 (− ) a,c − 30.6 (− ) a,c Note: Number of decimals are reported as the authors have reported it. In case two or more decimals are given, one decimal is reported. For the objective measu res, a decrease (a negative value), mea ns a worse restricted mouth opening. For the subjective measures, an increase (a positive value), means a worse restricted mouth opening. Abbreviations: 3D-RT, three-dimensional radiotherapy; (n)W, number of weeks after oncological treatment; (n)M, number of mo nths after oncologic al treatment; AJCC, stage according to American Joint Committee on Cancer; AT, after oncological treatment; BT, before oncological treatment; CRT, chemoradiotherapy; IMRT, intensity m odulated radiotherapy; ERF, extracorpo-real radiofrequency; RT, radiotherapy; SES, socioeconomic status. aSignificant (p <0.05). bSignificant in some analyses (p <0.05). cDiffer ence between mean scores calculated. dConversion centimeters to millimeters. Value represents median [interquartile range]. Value represents mean score (SD).
T A B L E 4 Prognostic factor models for restricted mouth opening Study (year) Outcome measure Method for including factor in model Performed analysis
Factors in the final model Estimated effect Bragante et al (2015)53 Reduction in maximal mouth opening Bivariate analysis (P < .20) Linear regression analysis Enter (P < .05) B 95% confidence interval Change in diet consistency
after radiotherapy
−0.29 −4.27;3.69 Radiation field—oral
cavity and oropharynx
−2.83 −6.61;0.96 Mucositis after
radiotherapya
−4.19 −7.62;−0.80 Difference in Karnofsky
Performance Scalea,b
0.12 0.02;0.24 Disease stage: III/IV −0.90 −4.26;6.07 Kamstra et al (2015)15 Change in maximal mouth opening Theoretical plausability Linear mixed model analysis Backward stepwise selection (P < .05) (−log likelihood criterion) B 95% confidence interval Intercept 12.88 10.00;15.77 Location Oral cavity 1.57 −3.50;6.63 Oropharynx and nasopharynx 1.04 −4.09;6.18 Salivary glands and ear 2.56 −2.57;7.68 Hypoglottic and
supraglottic larynx
3.56 −1.61;8.73 Glottic and subglottic
larynx
4.40 −0.76;9.57 Nasal cavity and maxillary
sinus
1.26 −4.00;6.53
Unknown primary - N/A
Time after radiotherapy 4.00 3.38;4.63
Male sex 1.10 0.11;2.08
Mouth opening before treatment
0.69 0.65;0.73 Tumor stage: T4 −1.14 −2.16;−0.11
Age −0.05 −0.08;−0.01
Target volume on primary tumor
−4.76 −9.36;−0.17 Oral cavity× time 0.69 −0.47;1.85 Oropharynx or nasopharynx× time 0.47 −0.70;1.64 Salivary glands or ear× time 0.91 −0.26;2.08
limited, or conflicting levels of evidence. Levels of strong evidence were not reached. Nonetheless, this systematic review gives insight into the factors that should be taken into account in future research on a restricted mouth opening in patients with head and neck cancer.
4.3
|
Prognostic factors
Moderate evidence was found for the influence of
mucositis after radiotherapy on a reduction in MMO.53
The effect of mucositis on mouth opening is probably related to the associated healing tendency and the asso-ciated pain, since it was noted that MMO decreased in the presence of mucositis and increased when the
mucositis resolved.78The effects of pain on MMO,
ana-lyzed in the form of pain medication or alcohol (which may act as a pain killer as well) have also been
reported.16,47,48 The effects of factors related to the
healing tendency or pain intensity on a restricted mouth opening should be explored further in future studies. T A B L E 4 (Continued) Study (year) Outcome measure Method for including factor in model Performed analysis
Factors in the final model Estimated effect Hypopharynx or supraglottic larynx× time 1.27 0.09;2.45 Glottic or subglottic larynx× time 1.48 0.30;2.66 Nasal cavity or maxillary
sinus× time
0.62 −0.57;1.82 Unknown primary× time - N/A Mouth opening before
treatment× time
−0.10 −0.11;−0.09 Male sex× time 0.32 0.11;0.54 Baseline age centered at
60 years× time
−0.01 −0.02;0.00 Tumor stage T4× time −0.27 −0.50;−0.05 Target volume on primary
tumor× time −1.69 −2.75;−0.64 Dzioba et al (2017)76 EORTC QLQ HN35c Mixed effect regression analysis P> .05 exclusion interaction terms P> .05 exclusion for treatment B 95% confidence interval Baseline 14.65 7.4;21.9 Surgery and radiotherapy 2.24 −7.6;12.0 Surgery and
chemoradiotherapy
14.59 5.5;23.7 1 month after treatment 12.42 5.2;19.6 6 months after treatment 11.30 3.7;18.9 1 year after treatment 2.86 −5.3;11.0
a
Significantly contributing to the model.
bKarnofsky Performance Scale: an index used to classify functional impairment, using a scale of 0-100.
cThe European Organization for Research and Treatment of Cancer Quality of Life Questionnaire—Head and Neck cancer Module 35: a
T A B L E 5 Best evidence synthesis of prognostic factors on MMO and on scores for perceived difficulties opening the mouth
Prognostic factor Studies
Number of patients per study Total number of patients Associations (+,−, or ±) Level of evidence Maximal mouth opening reduction
Disease stage [54;57;53] 26;29;56 111 − Moderate
Presence of mucositis [53;53] 56 56 + Moderate
Deterioration of overall functioning (Karnofsky Performance Status Scalea)
[53] 56 56 + Moderate
Diet consistency [53] 56 56 − Moderate
Larger target volume [15] 641 641 + Limited/Moderate Shorter time after treatment [15] 641 641 + Limited/Moderate Smaller baseline mouth
opening
[15] 641 641 + Limited/Moderate
Localization [16;53;15] 143;56;641 840 + Conflicting
Oral cavity (predominantly maxilla) and oropharynx vs other localizationsb 54 26 26 ± [14;57;53c] 64;29;56 149 − Age [15] 641 641 + Conflictingb [14] 64 64 − T classification [15] 641 641 + Conflicting
T classification stage 4 vs other stages.b
[14;16] 64;143 207 −
Reconstruction [58] 65 65 + Conflicting
Platysma flap vs submental flapb
[14;16] 64;143 207 −
Treatment modalities [16;43] 143;16 159 + Conflictingb
Multiple treatment modalities vs single treatment modality; (Chemo) radiotherapy vs surgery > 6months [14;55] 64;96 160 ± [54] 26 26 − Sex [15] 641 641 + Conflicting [14] 64 64 ± [16;62] 143;372 515 −
Dental status [14;16] 64;143 207 − Limited
Alcohol [16] 143 143 − Limited
Smoking [16] 143 143 − Limited
N classification [14] 64 64 − Limited
−509 genotype [56] 62 62 ± Limited
The healing process might also influence the impact of other factors (such as time after treatment and different types of treatment modalities) on a restricted mouth open-ing. If time passes, it is likely that the affected tissues will heal. The MMO might become less restricted or even
increase over time.15The healing process might also differ
per treatment modality. For instance, in one study, the dif-ferences in MMO reduction between surgery and (chemo) radiotherapy over time were displayed: patients who had surgery had a decrease in MMO directly after treatment, but the MMO increased in the 6 months thereafter, whereas the patients who received (chemo) radiotherapy had a decrease in MMO directly after treatment, but the MMO did not increase in the 6 months thereafter. The healing process after (chemo) radiotherapy takes more time
than after surgery.14
Besides the healing process, tumor localization might influence MMO as well, although the evidence is con-flicting. The greatest reduction in MMO is most likely when the tumor is located near risk structures. Risk structures involve the temporomandibular joint and the masticatory muscles. A decrease in MMO and an increase in perceived difficulties with opening the mouth
were found when the tumor was located in proximity of these risk structures, such as the oral cavity, oropharynx and nasopharynx, nasal cavity, and maxillary sinus. A former systematic review on risk factors for trismus
included only one study (the Goldstein et al51) that found
that the MMO was reduced by 18% (SD 17%) when the temporomandibular joint and/or the pterygoid muscles
were affected.9A later review concluded that the
mastica-tory related structures generally affect MMO, but the
masseter muscle had the strongest influence.79 More
recently, the ipsilateral medial pterygoid muscle19,80and
the masseter muscle49,80were identified as the structures
most likely to result in a decrease in MMO.
A larger target volume, and also a stage IV tumor,
resulted in a large reduction of MMO.15Both findings are
in contrast with other studies.14,16,54,57,65 Presumably, a
significant effect was found for such a large tumor, because more risk structures were involved and more extensive cancer treatment was necessary.
There is limited to moderate evidence that baseline
mouth opening affect MMO.15A smaller baseline mouth
opening results in a larger decrease in MMO. This large decrease in MMO means that the risk of trismus will be T A B L E 5 (Continued)
Prognostic factor Studies
Number of patients per study Total number of patients Associations (+,−, or ±) Level of evidence Increased score on perceived difficulties opening the mouth
Shorter time after treatment [76] 117 117 + Limited/moderate Treatment modalities [74;76] 111;117 228 − Conflicting
Multiple treatment modalities vs single treatment modality; Chemo radiotherapy vs radiotherapy; Three dimensional radiotherapy vs intensity modulated radiotherapy >6 monthsb [35;71] 241;60 301 ±
Higher social economic status [46] 161 161 + Limited No addition of electrofrequency [72] 83 83 + Limited Localization [65] 80 80 − Limited T stage [65] 80 80 − Limited
Note:[number], reference of study, univariate analysis; [number], reference of study, multivariate analysis; +, significant association found between factor and outcome measure;−, no significant association found between factor and outcome measure; ±, partial association found between elements within a factor and outcome measure.
aKarnofsky Performance Scale: an index used to classify functional impairment, using a scale of 0-100.
bSignificant associations found between factor and outcome measure on the basis of a particular categorization. This particular categorization
is written in italics.
cThis study analyzed the effects of“radiation field in the area of the oral cavity and oropharynx” on maximal mouth opening, and is therefore
greater. As an elaboration of this found effect, a baseline mouth opening of 46 mm or less was determined, as a
cut-off point for developing trismus.80
The described effects of sex and age on MMO are con-flicting. One study found that males tend to have a larger
decrease over time than females.14 Another study found
that the decrease was the same in males and females over
time.16Yet another study found that females had a higher
risk of a decrease in mouth opening than males.15
Regard-ing age, one study found that the mouth openRegard-ing of youn-ger patients decreased more over time than of older
patients.14 However, another study found that older
patients had a higher risk of a decrease in mouth opening
than younger patients.15 The effects of sex and age may
have been confounded by other factors not reported or analyzed in those studies. For instance, the genotype of
the patients might have influenced the effect.56 Patients
with the homozygous TT −509 genotype experienced a
greater reduction in MMO than patients with the
homozy-gous CC or heterozyhomozy-gous CT−509 genotype. However, the
evidence for the influence of the−509 genotype is limited.
4.4
|
Objective and subjective measures
over time
Diverse patterns were seen over time regarding perceived difficulties with opening the mouth. Patients' perceptions F I G U R E 2 A, Longitudinal evaluation of percentage of patients with trismus. * indicates that study reported trismus as a secondary outcome. Broken lines display studies that had overlapping data with other studies. The studies that contained the largest sample size are displayed as straight lines. B, Longitudinal evaluation of maximal mouth opening. Broken line displays studies that had overlapping data with other studies. The studies that contained the largest sample size are displayed as straight lines. C, Longitudinal evaluation of patient's quality of life score-domain: difficulties opening the mouth. * indicates that study reported patient's score of perceived difficulties opening the mouth as a secondary outcome. Broken lines display studies that had overlapping data with other studies. The studies that contained the largest sample size are displayed as straight lines
of difficulties with opening the mouth might be influenced by different factors over time, such as pain, dry mouth,
overall emotional functioning, or treatment modalities.81,82
4.5
|
Strength and limitations
The strength of this study is that we had no restriction concerning publication year or publication language. Four databases were searched in order to include as many stud-ies as possible. Due to the different aims of the studstud-ies and subsequently the different designs of the studies, it was challenging to structure and interpret the data. Due to clinical and methodological heterogeneity, no meta-analy-sis was conducted. Instead, we performed a best evidence synthesis. Due to this synthesis, we were still able to gain insight into which prognostic factors should be taken into account from the 53 included studies. The results of this systematic review should be viewed cautiously because of high risk of bias in the source studies.
We used the QUIPS tool to assess bias but it was not really suitable for those studies whose primary aim was not to analyze trismus prognostic factors, making it diffi-cult to assess the studies. Hence, the overall kappa score was low.
4.6
|
Future research
Large sample size studies are recommended with multi-ple structured measurement moments to analyze prog-nostic factors. The effects of factors related to healing tendency and pain intensity on trismus, decrease in MMO, and perceived difficulties with opening the mouth should be studied further.
5
|
C O N C L U S I O N
A restricted mouth opening is most likely when the patient with head and neck cancer has a large tumor located in close proximity to the mastication muscles or temporomandibular joint that requires extensive cancer treatment. A restricted mouth opening will most likely occur in the first 6 months after cancer treatment. More research is needed on the effect of factors related to healing tendency and pain intensity on a restricted mouth opening.
A C K N O W L E D G M E N T S
We would like to thank S. van der Werf for her assistance with building the best possible search strategy for this review; K. Delli and B. Gareb for their input and
assessment of risk of bias; K.C. Bragante and J.W. Wetzels for sharing data of their studies, X. Lu for trans-lation of an article.
C O N F L I C T O F I N T E R E S T
The authors declare no potential conflict of interest.
O R C I D
Sarah J. van der Geer
https://orcid.org/0000-0002-5766-054X
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